Department of Radiation Oncology
Jay R. Harris, MD, Chair
The Department of Radiation Oncology at Dana-Farber is committed to combining advances in clinical and laboratory research with developments in radiation physics to promote not only a better understanding of the biology of cancer and normal tissues but also improved treatment of cancer. The department is part of the combined effort in Radiation Oncology between DFCI, Brigham and Women's Hospital, and Children's Hospital Boston. The laboratory for the combined department is located at DFCI.
Our laboratory research is focused on the treatment of tumors by ionizing radiation and ultimately improving therapy through understanding radiation and other treatments at the molecular and cellular levels. Although the basic physical and biochemical mechanisms underlying radiation therapy are understood, only recently have we been able to grasp the molecular and tissue-level responses that determine tumor cell fate during treatment. We continue to make advances in our knowledge of the radiation response of tumor cells in tissue culture and within tumors.
Alan D'Andrea, MD, is studying the molecular signaling pathways that regulate the DNA damage response in mammalian cells. Disruption of these pathways, by germline or somatic mutation, leads to genomic instability and cellular sensitivity to ionizing radiation, as well as defective cell-cycle checkpoints and DNA repair. These pathways are often disrupted in cancer cells, accounting for the chromosome instability and increased mutation frequency in human tumors. Dr. D'Andrea's primary focus is the molecular pathogenesis of the human chromosome instability syndromes: Fanconi anemia (FA), ataxia-telangiectasia, and Bloom syndrome. FA is an autosomal recessive cancer susceptibility disorder characterized by developmental defects and increased cellular sensitivity to DNA crosslinking agents. Eleven FA genes have been cloned, and the encoded FA proteins interact in a novel signaling pathway. Seven FA proteins (A, C, E, F, G, L, M) form a nuclear protein complex required for the monoubiquitination of the D2protein. Activated D2 is targeted to chromatin, where it interacts with the products of the breast cancer susceptibility genes, BRCA1 and BRCA2. Our research program addresses several aspects of this novel signaling pathway including: (1) the assembly, transport, and structure of the FA protein complex; (2) the enzymatic monoubiquitination and deubiquitination of the D2 protein; (3) the function of the chromatin-associated FA complex in cell cycle checkpoints and homologous recombination DNA repair; and (4) the identification of novel interacting proteins in these complexes.
Mike Makrigiorgos, PhD, is studying mutation and genomic instability induced by radiation or other agents. His laboratory has developed a range of methodologies for evaluation of tumor-specific genetic changes, on a genomewide scale. A new method, called balanced polymerase chain reaction (bal-PCR), amplifies laser-capture microdissected tumor samples in an unbiased manner prior to molecular profiling, thus enabling the microarray screening of minute tumor biopsies. In addition, a novel, highly selective assay - inverse PCR-based fragment length polymorphism (iFLP) - provides high-throughput screening of mutations and polymorphisms in tumors and human tissues, allowing the identification of genomic instability at the nucleotide level, at early stages of tumor development. This early detection of genomic instability should provide a better understanding of tumor biology and may result in an early screening test for cancer.
The ataxia-telangiectasia gene (ATM) has emerged as the central molecular regulator of the radiation response, mediating cell cycle arrest and DNA repair after radiation. Brendan Price, PhD, has made major advances in understanding the role of the ATM protein as a sensor of DNA damage and a regulator of radiation resistance in the irradiated cell. He has demonstrated that ATM phosphorylates specific residues of the p53 protein after DNA damage. Further, Dr. Price has identified several regulatory domains within the ATM protein, including a leucine zipper domain in the central portion of the protein and a substrate-binding domain at the extreme N terminus of the protein. These findings offer great potential in the rational design of combination cancer therapy specifically targeting the ATM protein and its substrates.
The utility of radiation therapy in the clinic is limited by normal tissue toxicity, and hematopoietic stem cells are an important limiting tissue for radiotherapy. Peter Mauch, MD, is studying how cytotoxic therapy affects the viability and stem cell capacity of hematopoietic stem cells and has developed systems to determine the effects of treatments on hematopoiesis. In particular, he is studying very early stem cells, designated as "side population cells," in mice. In the clinic, he and his colleagues are developing assays to assess the loss of marrow reserve capacity. Dr. Mauch's studies are of particular relevance for treatments involving high-dose chemotherapy and whole-body irradiation followed by marrow rescue and repopulation with hematopoietic stem cells.
